Subsequent cancers in patients diagnosed with cancer of unknown primary (CUP): etiological insights?

BACKGROUND: Patterns of subsequent malignancies in patients with cancer of unknown primary (CUP) may provide etiological insight into the primary tumor. The objective of the present study is to quantify risks of the subsequent cancers in CUP patients since such studies are lacking. PATIENTS AND METHODS: A population-based cohort of CUP was identified from the Swedish Family-Cancer Database of year 2008. Standardized incidence ratios (SIRs) were calculated for developing the following malignancies in 31 357 CUP patients from 1975 to 2008. RESULTS: A total of 755 CUP patients developed subsequent cancers, showing a significantly increased overall SIR of 1.69 (95% confidence interval 1.57-1.81). Among the most common 32 malignancies, increased SIRs were noted for 16 sites. Over 10-fold increases were observed for squamous cell carcinoma at four sites, possibly as a result of uncontrolled human papillomavirus infection due to faltering immune surveillance. The highest SIRs were observed among CUP patients diagnosed at a younger age and during the first follow-up year. CONCLUSIONS: Swedish CUP survivors had a higher risk of developing many subsequent cancers. Different patterns of risk excess may be suggestive of possible roles for disease- and therapy-related immunosuppression, reappearance of hidden primary tumors, or genetic predisposition.